Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma.
Aspirin causes bronchoconstriction in aspirin-intolerant asthma (AIA) patients by triggering cysteinyl-leukotriene (cys-LT) production, probably by removing PGE2-dependent inhibition. To investigate why aspirin does not cause bronchoconstriction in all individuals, we immunostained enzymes of the leukotriene and prostanoid pathways in bronchial biopsies from AIA patients, aspirin-tolerant asthma (ATA) patients, and normal (N) subjects. Counts of cells expressing the terminal enzyme for cys-LT synthesis, LTC4 synthase, were fivefold higher in AIA biopsies (11.5+/-2.2 cells/mm2, n = 10) than in ATA biopsies (2.2+/-0.7, n = 10; P = 0. 0006) and 18-fold higher than in N biopsies (0.6+/-0.4, n = 9; P = 0. 0002). Immunostaining for 5-lipoxygenase, its activating protein (FLAP), LTA4 hydrolase, cyclooxygenase (COX)-1, and COX-2 did not differ. Enhanced baseline cys-LT levels in bronchoalveolar lavage (BAL) fluid of AIA patients correlated uniquely with bronchial counts of LTC4 synthase+ cells (rho = 0.83, P = 0.01). Lysine-aspirin challenge released additional cys-LTs into BAL fluid in AIA patients (200+/-120 pg/ml, n = 8) but not in ATA patients (0. 7+/-5.1, n = 5; P = 0.007). Bronchial responsiveness to lysine-aspirin correlated exclusively with LTC4 synthase+ cell counts (rho = -0.63, P = 0.049, n = 10). Aspirin may remove PGE2-dependent suppression in all subjects, but only in AIA patients does increased bronchial expression of LTC4 synthase allow marked overproduction of cys-LTs leading to bronchoconstriction.
Cowburn
A S
AS
University Medicine, Immunopharmacology Group, Southampton General Hospital, Southampton, SO16 6YD, United Kingdom.
Sladek
K
K
Soja
J
J
Adamek
L
L
Nizankowska
E
E
Szczeklik
A
A
Lam
B K
BK
Penrose
J F
JF
Austen
F K
FK
Holgate
S T
ST
Sampson
A P
AP
D001241:Aspirin / Q000009:adverse effects*; D001249:Asthma / Q000139:chemically induced / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D001706:Biopsy; D001980:Bronchi / Q000201:enzymology* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016207:Cytokines / Q000096:biosynthesis; D004804:Eosinophils / Q000276:immunology; D005260:Female; D005982:Glutathione Transferase / Q000096:biosynthesis*; D006801:Humans; D007958:Leukocyte Count; D015289:Leukotrienes / Q000096:biosynthesis; D008297:Male; D010919:Placebos / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology
D016207:Cytokines; D015289:Leukotrienes; D010919:Placebos; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase; D001241:Aspirin